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L0301P33 - Multifactorial Inheritance
Polygenic Inheritance *several genes located at different loci that contribute to the aetiology (cause) of the condition or disease Multifactorial Inheritance *the effects of multiple genes influenced by the pre- and post- natal environment *caused by a number of genes at different loci which have a small additive effect together with environmental factors *e.g. height, skin colour, blood pressure, diabetes Monogenic vs Polygenic Disorders *monogenic **determined by one gene **as a simple inheritance pattern *polygenic **determined by several genes **has a complex inheritance pattern **involves lifestyle and environment Multifactorial Disorders Congenital Malformations *cleft palate *congenital heart defects *neural tube defects *pyloric stenosis Acquired Diseases in ChIldhood and Adult Life *asthma *autism *epilepsy *diabetes mellitus *hypertension *ischaemic heart disease *manic depression *schizophrenia *cancer Characteristics of Multifactorial Diseases *affected children may have normal parents (low penetrance of gene) *environmental risk **particularly nutritional deficiency and maternal smoking in cleft lip birth defect *risk is greater if more than one family member is affected ( if disease is severe) *can occur more frequently in one gender (not sex linked) *risk decreases as degree of relationship decreases Multifactorial Traits Continous (quantitative) *does not have a discrete phenotype *environmental factors interface with many genes to generate a continuous distortion in the population (normal distribution) *e.g. height, intelligence, skin colour Discontinuous (qualitative) *discrete phenotypes (i.e. affected or not affected) *e.g. autism, diabetes Recurrence Risk for Multifactorial Traits *usually based on information collected from observations of a large series of affected individuals and families **specific to each disorder and may vary between populations *recurrence risk is higher if: **more than one family member affected **affected individual is of the less commonly affected sex **severity of the disease in the individual is more severe *risk of recurrence calculated in first degree relatives Heritability *estimate of the proportion of the variability in a trait that is due to genetic rather than the environment Genetic Epidemiology *identify the exact genes that contribute to the aetiology of the disease condition AND *distinguish genetic and environmental features *using: twin studies and adoption studies Twin Studies *monozygotic (MZ) **single zygote and genetically identical **any differences between them should be a result of environment rather than genetic factors *dizygotic (DZ) **arise from fertilisation of two eggs by different sperm **different genetically and more like siblings Traits *concordant **share a trait - 100% monozygotic *discordant **do not share a trait Examples 1. Autism *neurodevelopmental disorder *onset within the first 3 years of life *absence of verbal communication, lack of social responsiveness, developmental delay *twin studies: **genetic component **concordance rate - 80% in MZ, 3% in DZ **familial aggregation **>15 susceptibility loci: additive effect 2. Pyloric Stenosis *muscles in the lower portion of the stomach that connects to the small intestine enlarge, narrowing the opening of the pylorus and eventually stops food from moving from stomach to the intestine *causes forceful vomiting —> dehydration *affects many newborns *more common in males and Caucasians *twin studies: **may be inherited **25-40% concordance rate in MZ twins 3. Diabetes Mellitus Type I *insulin dependent DM *juvenile onset *concordance - 50% MZ, 12% DZ *>18 diabetes-predisposing genes have been reported to date Type II *non-insulin dependent DM *mature onset *concordance is higher among MZ twins *environmental factors - low birth weight *increasing prevalence mirrors the increase in obesity worldwide 4. Coronary Artery Disease *major cause of morbidity and mortality *results from atherosclerosis, leading to myocardial infarction *environmental factors - poor diet, cigarette smoking, stress *twin studies: **familial aggregation **39-48% MZ, 15-25% DZ Epistasis *gene interaction where an allele at a particular locus alters the phenotypic expression of another non-allelic gene *i.e. phenotypic expression of one gene is influenced by another gene *e.g. colour and eye colour of animals *E.g.: hair colour gene and pigment deposition gene interact for dog coat colour